This invention relates to N-heterocyclic derivatives of thienamycin and their pharmaceutically acceptable salt and ester derivatives. Such compounds are useful as antibiotics and may be represented by the following generic structural formulae I and II: ##STR2## wherein: the bifunctional radical may contain additional unsaturation in the ring; and wherein n is an integer selected from 1-6; p is 0, 1 or 2; R.sup.1 is selected from hydrogen, alkyl having 1-6 carbon atoms, and aryl having 6-10 carbon atoms; and Z is imino (.dbd.NH), oxo (.dbd.O), hydrogen, amino, or alkyl having 1-6 carbon atoms. Such compounds and their pharmaceutically acceptable salt and ester derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
Preferred compounds of this invention are represented by the structural formula: ##STR3## and the pharmaceutically acceptable salts thereof; wherein: R.sub.1 is hydrogen, alkyl having from 1-6 carbon atoms or phenyl;
X is imino or oxo; PA1 Y is hydrogen or alkyl having from 1-6 carbon atoms; PA1 Z is hydrogen, alkyl having from 1-6 carbon atoms PA1 or alkoxycarbonyl having from 2-7 carbon atoms; and tautomers thereof where Y or Z is hydrogen, and X is amino. PA1 Methyl N-cyanomethyl formimidate, PA1 ethyl N-cyanomethyl formimidate, PA1 methyl N-cyanoethoxycarbonylmethyl formimidate, PA1 ethyl N-cyanocarbamoylmethyl formimidate, PA1 methyl N-.alpha.-cyanoethyl formimidate, PA1 ethyl .alpha.-cyanoisopropyl formimidate, PA1 methyl N-.beta.-cyanoethylformimidate, PA1 methyl N-cyanomethylacetimidate, PA1 methyl N-.alpha.-cyanoisopropylacetimidate, PA1 ethyl N-cyanomethylpropionimidate, PA1 ethyl N-.beta.-bromoethylacetimidate, PA1 methyl N-.beta.-chloroethylformimidate, PA1 methyl N-.gamma.-bromopropylacetimidate, PA1 ethyl N-.gamma.-iodopropylformimidate, PA1 ethyl N-methoxylcarbonylmethyl formimidate, PA1 methyl N-.beta.-ethoxylcarbonylethylacetimidate, PA1 ethyl.beta.-cyanopropionimidate, PA1 methyl .gamma.-cyanobutyrimidate, PA1 methyl .gamma.-bromobutyrimidate, PA1 ethyl N-methyl valerimidate, PA1 methyl N-cyanomethylbenzimidate, PA1 ethyl N-cyanophenylmethyl formimidate; and the like.
This invention also relates to processes for the preparation of such compounds (I and II); pharmaceutical compositions comprising such compounds; and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
Thienamycin (III) is disclosed and claimed in U.S. Pat. No. 3,950,357, issued Apr. 13, 1976. This patent is incorporated herein by reference since thienamycin may serve as a starting material for the preparation of the compounds of the present invention (I and II, above): ##STR4##
Thienamycin and all of its isomers (in pure form and as mixtures) are also obtainable by the total synthesis disclosed and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 833,210 (Sept. 15, 1977). This application is incorporated herein by reference to the extent that it makes available all isomers of III as starting materials in the preparation of the compounds of the present invention.
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.